Selective Photoinactivation of Methicillin-Resistant Staphylococcus aureus by Highly Positively Charged RuII Complexes

Article abstract of DOI:10.1002/chem.201903923

Ruthenium(II) polypyridyl complexes featuring peripheral quaternary ammonium structures were found to be able to selectively inactivate Gram-positive Staphylococcus aureus (S. aureus), including methicillin-resistant S. aureus (MRSA) upon visible light irradiation, but have low phototoxicity toward 293T cells, L02 cells and lack hemolysis toward rabbit red blood cells (RBC), exhibiting promising potential as a novel type of antimicrobial photodynamic therapy (aPDT) agents.

Full text of DOI:10.1002/chem.201903923

DOI: 10.1002/chem.201903923
Communication
&
Antimicrobial Agents
Selective Photoinactivation of Methicillin-Resistant Staphylococcus
II
aureus by Highly Positively Charged Ru Complexes
[a, b]
[a, b]
[a, b]
[a]
Yang Feng,
Wei-Ze Sun,
Xue-Song Wang,*
and Qian-Xiong Zhou*
[8]
fectively. The multi-target feature of ROS not only renders
aPDT highly potent in killing even multidrug resistant bacteria,
but also makes bacteria difficult to develop any resistance
Abstract: Ruthenium(II) polypyridyl complexes featuring
peripheral quaternary ammonium structures were found
to be able to selectively inactivate Gram-positive Staphylo-
coccus aureus (S. aureus), including methicillin-resistant S.
aureus (MRSA) upon visible light irradiation, but have low
phototoxicity toward 293T cells, L02 cells and lack hemoly-
sis toward rabbit red blood cells (RBC), exhibiting promis-
ing potential as a novel type of antimicrobial photody-
namic therapy (aPDT) agents.
[9–11]
against these multiple attacks.
However, the same modes of action of PDT and aPDT raise a
great challenge in selectively inactivating bacterial cells but
leaving mammalian cells unaffected. Unlike mammalian cells,
in which acidic phospholipids are mainly located in the inner
leaflet of plasma membranes, acidic phospholipids and nega-
tively charged components, such as teichuronic acid (for Gram
positive bacteria, for example, S. aureus) and lipopolysaccha-
ride (for Gram negative bacteria, for example, E. coli) are
mainly located in the outer edges of cell walls or outer mem-
branes, making the bacterial surface highly negatively
The widespread use of antibiotics has led to severe antibiotic
resistance worldwide. A typical example is Staphylococcus
aureus, one of the most common causes of nosocomial infec-
tions and community-acquired infections. Since methicillin-re-
sistant S. aureus (MRSA) appeared 50 years ago, S. aureus so far
has evolved to be resistant to nearly all clinically approved an-
[
12,13]
charged.
ionic aPDT agents, such as triarylmethanes
dipyrromethene (BODIPY) dyes bearing two positive charges,
This disparity has been leveraged to develop cat-
[14,15]
and boron-
[16]
[17]
[18–23]
perylene bearing four positive charges,
porphyrins,
bearing three, four,
[
1]
[2]
[3]
[24]
[25,26]
tibiotics, including vancomycin, clindamycin, mupirocin,
phthalocyanines and bacteriochlorin
[
4]
and linezolid, some of which are recognized to be the last
resort for the multidrug resistant pathogens. This fact makes
S. aureus one of the most formidable pathogens. In view of its
high infection opportunity, particularly for the hospitalized pa-
tients, new types of antibacterial agents or therapies not easy
to elicit resistance are urgently and desperately needed for dis-
or eight positive charges, with the aim to achieve higher bind-
ing affinity toward bacteria. Though these photosensitizers
showed remarkable inactivation capability against bacterial
cells, in several cases, phototoxicity toward mammalian cells
[14,23]
was observed,
suggesting limited selectivity of the aPDT
agents. For example, a triarylmethane dye reduced CFU of E.
coli by 5log units at 1 mm upon irradiation, but only 60% A549
[
5–7]
infection of S. aureus.
[14]
While the rapid intrinsic mutation and horizontal gene trans-
fer are responsible for resistance emergence and dissemination
among bacteria, from the viewpoint of antibiotics, their single-
target character is also a reason to allow bacteria to readily de-
velop resistance strategies. In this regard, photodynamic thera-
py (PDT), a clinical tumor treatment modality, displays promis-
ing potential in antibacterial applications as well, the so-called
antimicrobial photodynamic therapy (aPDT). Both PDT and
cells were alive under the same conditions. Cationic porphy-
rins conjugated with an antimicrobial peptide caused complete
killing of S. aureus at concentrations below 2 mm upon blue
light irradiation, however, more potent activity against human
normal skin fibroblast cells was observed, with IC values
5
0
[23]
below 10 nm.
The poor selectivity was attributed to the
highly lipophilic porphyrin cores which lead to strong interac-
tion with both mammalian and bacterial membranes. Hamblin
and co-workers found cationic porphyrins were taken up more
rapidly by microbial cells than mammalian cells, which was uti-
lized to improve selectivity by a short incubation time
aPDT inactivate cells by photosensitized generation of reactive
1
oxygen species (ROS). ROS, mainly singlet oxygen ( O ), are
2
highly reactive and can damage DNA, proteins, and lipids ef-
[
25,26]
(
30 min),
but will complicate clinical application. In most
the selectivity between bacterial and mammalian
[
16–22,24]
cases,
[
a] Dr. Y. Feng, Dr. W.-Z. Sun, Prof. X.-S. Wang, Prof. Q.-X. Zhou
Technical Institute of Physics and Chemistry
Chinese Academy of Sciences, Beijing 100190 (P.R. China)
E-mail: xswang@mail.ipc.ac.cn
cells of these aPDT agents was not reported.
To reveal the positive charge effect on aPDT, we turn our at-
II
tention to the Ru polypyridyl complexes not only due to their
zhouqianxiong@mail.ipc.ac.cn
1
high O2 yields, long luminescence lifetimes, and excellent
[b] Dr. Y. Feng, Dr. W.-Z. Sun, Prof. X.-S. Wang
[27,28]
chemical stability and photostability,
but also and more
University of Chinese Academy of Sciences, Beijing 100049 (P.R. China)
importantly due to their modular assembly manner of their
structures as well as their properties. While Ru-based PDT
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201903923.
[29]
agents have entered clinical trials, their aPDT potency may
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[
34]
1
also be facilely modulated. In this work, using quaternary am-
with similar structures. The lower O quantum yield of Ru1
2
II
monium-modified bipyridine as ligand, three new Ru com-
may result from its shorter excited state lifetime.
plexes Ru1–Ru3 with four, six, and eight positive charges
Antibacterial performances of the complexes against S.
aureus and MRSA are presented in Figure 2. In the dark, all ex-
amined complexes did not affect the growth of S. aureus (Fig-
(
Figure 1) were easily prepared. The spherical octahedral coor-
II
dination structure and hydrophilic cationic character of the Ru
core may distinguish them from the reported organic aPDT
ure 2B). Upon light irradiation at 470 nm for 20 min (LED,
À2
2
2.5 mWcm ), Ru1–Ru3 showed concentration-dependent
bactericidal effect against S. aureus (Figure 2a). At 15 mm, Ru3
led to a colony-forming unit (CFU) reduction of 6.87 log units,
much higher than Ru1 (4.15 log units) and Ru2 (4.10 log units).
The CFU reduction can be directly observed on 3m Petrifilm
2
+
Aerobic Count Plates (Figure S6). In sharp contrast, Ru(bpy)3
exhibited negligible antibacterial activity in the same condi-
tions, demonstrating the key roles of the peripheral positive
charges. Obviously, more positive charges that Ru1–Ru3 bears
facilitate their binding toward negatively charged S. aureus,
1
and improve bioavailability of O .
2
It is worth noting that complex Ru3 exhibited remarkable
photoinactivation capability against MRSA. As shown in Fig-
ure 2C, the CFU reduction by Ru3 (15 mm) was still as high as
Figure 1. Chemical structures of complexes Ru1, Ru2, and Ru3.
5
.75 log units. We also compared the anti-MRSA performance
[
14–23]
agents,
which generally have large planar conjugated and
of Ru3 with that of traditional antibiotics, methicillin and van-
comycin (Figure 2D). As expected, MRSA showed resistance to
methicillin, but was eradicated effectively by vancomycin. At
10 mm of vancomycin, a CFU reduction of 5.89 log units was
observed. The comparable bactericidal ability of Ru3 demon-
strates again the important role of the peripheral positive
charges that a Ru complex takes, which transforms a totally
II
highly hydrophobic skeletons, making these Ru complexes ef-
ficiently bind to bacteria but not mammalian cells. Our results
indicate that complex Ru3 bearing eight positive charges ex-
hibited the most potent aPDT activity against S. aureus, includ-
ing MRSA. Notably, all three complexes showed extremely low
toxicity toward mammalian cells even upon visible light irradia-
tion, indicative of their high selectivity.
2
+
inert [Ru(bpy)3] to a highly potent aPDT agent.
The detailed synthesis and structure characterization of the
complexes Ru1–Ru3 may be found in Supporting Information
Complexes Ru1–Ru3 can also inactivate E. coli under light ir-
radiation, but with less efficiency (Figure S7). The dense and
compact outer membranes of E. coli may hamper the photo-
damage from Ru1–Ru3. Interestingly, complex Ru2 displayed
the highest photoinactivation effect, the reason is unknown
yet.
(
[
SI). The normalized absorption and emission spectra of
2
+
Ru(bpy)3]
(abbreviated as Ru0) and Ru1–Ru3 in PBS are
shown in Figure S4 (SI). Ru1–Ru3 display redshifted MLCT
metal to ligand charge transfer) absorption and emission com-
(
pared with that of Ru0. The introduction of electron-withdraw-
ing bpy-TMEDA ligand in Ru1–Ru3 will lower the energy level
of p*(bpy-TMEDA)-based LUMO (lowest unoccupied molecular
orbital) more efficiently than that of t (Ru)-based HOMO (high-
Besides CFU measurements, we also examined the morpho-
logical changes of bacteria by SEM (Figure 3). S. aureus cells
(2 mL) in the exponential phase were harvested, 1 mL of which
was treated with Ru3 and then exposed to light irradiation.
The untreated S. aureus cells maintained their morphology in-
tegrity. However, the aPDT treated cells showed damaged and
deformed cell walls, and the leakage of intracellular compo-
nents may partially account for the death of S. aureus. The re-
sults suggest that the cell wall might be the target of Ru3,
which is in good agreement with the expected strong electro-
static attraction between highly positively charged aPDT
agents and highly negatively charged bacterial surfaces.
The binding/uptake of the complexes Ru1–Ru3 by bacterial
cells was measured with Inductively Coupled Plasma Mass
Spectrometric (ICP-MS). Bacteria suspension was incubated in
the dark in the presence of Ru complexes (10 mm) for 40 min.
After centrifugation to remove the supernatant, Ru content
was measured by ICP-MS. As shown in Table 1, the uptake in-
creased with the increase of positive charges from Ru1 to Ru3.
For complex Ru3, the binding/uptake level was measured to
2g
est occupied molecular orbital), thus leading to redshifted
MLCT absorption and emission. Similar results were also report-
II
ed for other electron-withdrawing groups modified Ru com-
[
30,31]
plexes.
With the number of bpy-TMEDA ligand increasing
from Ru1 to Ru3, the energy level of HOMO will be stabilized
further, whereas that of LUMO will be less affected, thus a
blueshifted emission is observed from Ru1 to Ru3. Similar to
1
their parent complex Ru0, whose O quantum yield in H O is
2
1
2
[
32]
0
.41, Ru1–Ru3 can also generate O efficiently. Using 3,3’-
2
1
(
anthracene-9,10-diyl)-dipropanoic acid (9,10-ADPA) as O trap-
2
[
33]
1
ping agent, which reacts with O in a quantitative fashion
2
1
to produce a non-absorbing/emitting compound, the O2
quantum yields were measured to be 0.32Æ0.03 for Ru1,
0
.40Æ0.05 for Ru2 and 0.38Æ0.04 for Ru3 in H O by monitor-
2
ing the absorption decay of 9,10-ADPA at 378 nm (Figure S5).
The luminescence lifetimes in H O were measured to be
2
8
5
66 ns for Ru0, 282 ns for Ru1, 517 ns for Ru2 and 847 ns for
be around 25 ng Ru/10 cells at the dose of 10 mm, consistent
with the antibacterial activity. z-potential measurements are in
II
Ru3, which is consistent with other reported Ru complexes
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Figure 2. (A,B) Antibacterial activity of Ru1–Ru3 and Ru0 against S. aureus with and without light irradiation. (C) Antibacterial activity of Ru1–Ru3 against
À2
MRSA with light irradiation (470 nm, LED, 22.5 mWcm , 20 min). (D) Antibacterial activity of methicillin, vancomycin in dark and Ru3 with light irradiation
(
470 nm, LED, 22.5 mWcmÀ2, 20 min) against MRSA. All data are expressed as meanÆs.d. of three replicates.
À2
Figure 3. SEM images of (A) untreated and (B) treated S. aureus cells by Ru3 (10 mm) for 1 h, followed by irradiation at 470 nm (LED, 22.5 mWcm ) for 20 min.
positive shift in z-potential was observed and the shift
Table 1. Binding/uptake of Ru1–Ru3 and their effects on z-potential of
strength follows the order of Ru3>Ru2>Ru1.
bacterial cells (data are mean values Æ standard deviation of three inde-
pendent experiments).
To reach clinical application, the toxicity of aPDT agents to
mammalian cells is an equally important factor. Notably, com-
plexes Ru1–Ru3 showed good biological compatibility irre-
spective of light irradiation. As shown in Figure 4A–C, very low
toxicity was observed for Ru1–Ru3 toward human uterine car-
cinoma HeLa cells up to a concentration of 80 mm, where the
cell viability of ca. 80% may be maintained even under visible
light irradiation. At the concentration of 15 mm, negligible tox-
icity was observed, particularly for complex Ru3. In sharp con-
trast, it can reduce CFU of S. aureus and MRSA by as high as
7 log units at the same concentration. The cytotoxicity of Ru1–
Ru3 on normal cells including 293T (human embryonic kidney
transformed 293 cells) and L02 (human hepatocyte cells) was
also studied, similar results were obtained (Figure S8). The low
8
Zeta potential [mV]
Binding/uptake [ng Ru/10 cells]
S. aureus
MRSA
S. aureus
MRSA
Blank
Ru1
Ru2
Ru3
À9.44Æ0.5
À10.3Æ0.5
–
–
À9.07Æ0.36 À9.64Æ0.06 3.58Æ0.17
À8.80Æ0.51 À8.59Æ0.38 3.73Æ0.22
À8.28Æ0.26 À7.94Æ0.54 25.40Æ2.63
3.22Æ0.25
3.78Æ0.41
27.55Æ3.09
line with the binding/uptake results. The average z-potential
values of S. aureus and MRSA were À9.44 and À10.30 mV, re-
spectively, in accordance with their negatively charged cell
walls. After incubated with the positively charged Ru com-
plexes, the negative charge density of cell walls was reduced, a
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Figure 4. (A–C) Cytotoxicity of Ru1, Ru2, and Ru3 toward HeLa cells, where “L” denotes light illumination and “D” denotes in the dark. (D) Hemolysis percent-
age of Ru1, Ru2, and Ru3 toward rabbit RBCs. All data are expressed as meanÆs.d. of three replicates.
cytotoxicity of Ru1–Ru3 may lie in their low cellular uptake
levels (Table S1), which are much lower compared with that of
bacterial cells. The low mammalian cell uptake levels of Ru1–
Ru3 are also consistent with their highly hydrophilic properties
phyrins and phthalocyanines, their large and planar aromatic
rings may aid in the interaction with cytoplasmic membranes.
In contrast, the spherical octahedron coordination structures of
II
the highly positively charged Ru polypyridyl complexes may
(
Table S1). The hemolysis experiments toward rabbit red blood
lack such an interaction and therefore have lower affinity
toward mammalian cells. Though still being a conjecture, the
high aPDT activity of Ru3 against MRSA in combination with
the low PDT activity toward mammalian cells fully demon-
strates the potential of such type of agents in the field of
aPDT.
cells (Figure 4D) also reveal the satisfactory biocompatibility of
Ru1–Ru3. The hemolysis rates were less than 1.8% even at
4
0 mm.
Finally, a co-culture experiment was performed to investi-
gate the selective photoinactivation of Ru3 toward bacterial
cells over mammalian cells. Mixed samples of S. aureus and
In summary, a highly selective aPDT agent toward MRSA
over mammalian cells was successfully achieved by simply in-
troducing six peripheral quaternary ammonium groups into a
2
93T were stained with PI and examined by confocal laser
scanning microscope (CLSM). As shown in Figure 5, in the pres-
ence of both Ru3 and irradiation, red fluorescence of PI can be
observed in S. aureus but not in 293T, indicative of dead bacte-
rial cells and live mammalian cells. Without irradiation, negligi-
ble red fluorescence was found in both types of cells (Fig-
ure S9). Clearly, the competitive binding of Ru3 toward S.
aureus is responsible for this observation, which in turn is the
result of the strong electrostatic interaction of Ru3 with highly
negatively charged bacterial cells.
II
typical Ru polypyridyl complex. The underlying mechanism
may shed light on the development of more effective and
more selective aPDT agents to tackle the increasingly emergent
antibiotic resistance crisis.
Acknowledgements
This work was financially supported by the National Key R&D
Program of China (2018YFC1602204), NSFC (21390400,
Though many types of highly positively charged organic
photosensitizers have been studied for aPDT application, their
phototoxicity toward mammalian cells was rarely exam-
21571181, and 21773277), and the Strategic Priority Research
Program of Chinese Academy of Sciences (XDB17000000).
[
14–24]
ined.
In a few cases, photodamage toward mammalian
[
14,23]
cells was observed.
For example, the cationic porphyrin-
cationic antimicrobial peptides (magainin and buforin) conju- Conflict of interest
gates exhibited strong interaction as well as photoactivity
[
23]
toward human fibroblasts. Besides the delicate balance be-
tween hydrophilicity and hydrophobicity, the molecular size
and shape might also play a role in the selectivity of a photo-
sensitizer. For cationic organic photosensitizers, such as por-
The authors declare no conflict of interest.
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Figure 5. CLSM images of the mixed solutions of S. aureus and 293T in the presence of Ru3 and light irradiation.
[
17] N. Niu, H. Zhou, N. Liu, H. Jiang, Z. Hu, C. Yu, Chem. Commun. 2019, 55,
395–4398.
Keywords: antimicrobial photodynamic therapy · methicillin-
resistant Staphylococcus aureus · reactive oxygen species ·
ruthenium(II) polypyridyl complexes · selectivity
4
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Manuscript received: August 27, 2019
Accepted manuscript online: August 30, 2019
Version of record online: && &&, 0000
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Communication
COMMUNICATION
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Antimicrobial Agents
Y. Feng, W.-Z. Sun, X.-S. Wang,*
Q.-X. Zhou*
&& – &&
Selective Photoinactivation of
Methicillin-Resistant Staphylococcus
aureus by Highly Positively Charged
Ru Complexes
Ruthenium(II) polypyridyl complexes
featuring peripheral quaternary ammo-
nium structures were found to be able
to selectively inactivate MRSA but have
extremely low cytotoxicity toward mam-
malian cells upon visible light irradia-
tion.
II
Chem. Eur. J. 2019, 25, 1 – 7
www.chemeurj.org
7
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ